Methods of Manufacturing Devices for the Neurorehabilitation of a Patient

ABSTRACT

A mouthpiece for providing non-invasive neuromodulation to a patient, the mouthpiece including an elongated housing having an anterior region and a posterior region, the elongated housing having a non-planar exterior top surface and internal structural members disposed within the housing, the internal structural members elastically responding to biting forces generated by the patient, a spacer attached to the top surface of the housing for limiting contact between a patient&#39;s upper teeth and the exterior top surface of the elongated housing, and a printed circuit board mounted to a bottom portion of the elongated housing, the printed circuit board having a plurality of electrodes for delivering subcutaneous local electrical stimulation to the patient&#39;s tongue.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.14/559,118, filed Dec. 3, 2014, now U.S. Pat. No. 9,656,060, which isincorporated by reference herein in its entirety.

FIELD OF THE INVENTION

In general, the invention relates to devices and methods fornon-invasive neurostimulation of a subject's brain. More specifically,the invention relates to devices and methods for non-invasiveneurostimulation of a subject's brain to effect treatment of variousmaladies.

BACKGROUND OF THE INVENTION

Traumatic brain injury (TBI) is a leading cause of disability around theworld. Each year in the United States, about two million people suffer aTBI, with many suffering long term symptoms. Long term symptoms caninclude impaired attention, impaired judgment, reduced processing speed,and defects in abstract reasoning, planning, problem-solving andmultitasking.

A stroke is a loss of brain function due to a disturbance in the bloodsupply to the brain. Every year, about 800,000 people in the UnitedStates will have a stroke. Stroke is a leading cause of long-termdisability in the United States, with nearly half of older strokesurvivors experiencing moderate to severe disability. Long term effectscan include seizures, incontinence, vision disturbance or loss ofvision, dysphagia, pain, fatigue, loss of cognitive function, aphasia,loss of short-term and/or long-term memory, and depression.

Multiple sclerosis (MS) is a disease that causes damage to the nervecells in the brain and spinal cord. Globally, there are about 2.5million people who suffer from MS. Symptoms can vary greatly dependingon the specific location of the damaged portion of the brain or spinalcord. Symptoms include hypoesthesia, difficulties with coordination andbalance, dysarthria, dysphagia, nystagmus, bladder and boweldifficulties, cognitive impairment and major depression to name a few.

Alzheimer's disease (AD) is a neurodegenerative disorder affecting over25 million people worldwide. Symptoms of AD include confusion,irritability, aggression, mood swings, trouble with language, and bothshort and long term memory loss. In developed countries, AD is one ofthe most costly diseases to society.

Parkinson's disease (PD) is a degenerative disorder of the centralnervous system, affecting more than 7 million people globally. Symptomsof PD include tremor, bradykinesia, rigidity, postural instability,cognitive disturbances, and behavior and mood alterations.

One approach to treating the long term symptoms associated with TBI,stroke, MS, AD, and PD is neurorehabilitation. Neurorehabilitationinvolves processes designed to help patients recover from nervous systeminjuries. Traditionally, neurorehabilitation involves physical therapy(e.g., balance retraining), occupational therapy (e.g., safety training,cognitive retraining for memory), psychological therapy, speech andlanguage therapy, and therapies focused on daily function and communityre-integration.

Another approach to treating the long term symptoms associated with TBI,stroke, MS, AD, and PD is neurostimulation. Neurostimulation is atherapeutic activation of part of the nervous system. For example,activation of the nervous system can be achieved through electricalstimulation, magnetic stimulation, or mechanical stimulation. Typicalapproaches focused mainly on invasive techniques, such as deep brainstimulation (DBS), spinal cord stimulation (SCS), cochlear implants,visual prosthesis, and cardiac electrostimulation devices. Only recentlyhave non-invasive approaches to neurostimulation become more mainstream.

Despite many advances in the areas of neurorehabilitation andneurostimulation, there exists an urgent need for treatments that employa combined approach, including both neurorehabilitation andneurostimulation to improve the recovery of patients having TBI, stroke,multiple sclerosis, Alzheimer's, Parkinson's, depression, memory loss,compulsive behavior, or any other neurological impairment.

SUMMARY OF THE INVENTION

The invention, in various embodiments, features methods and devices forcombining non-invasive neuromodulation with traditionalneurorehabilitation therapies. Clinical studies have shown that methodscombining neurostimulation with neurorehabilitation are effective intreating the long term neurological impairments due to a range ofmaladies such as TBI, stroke, MS, AD, and PD.

In one aspect, the invention features a mouthpiece for providingnon-invasive neuromodulation to a patient. The mouthpiece includes anelongated housing having an anterior region and a posterior region, theelongated housing having (i) a non-planar exterior top surface and (ii)internal structural members disposed within the housing, the internalstructural members elastically responding to biting forces generated bythe patient. The mouthpiece also includes a spacer attached to the topsurface of the housing for limiting contact between a patient's upperteeth and the exterior top surface of the elongated housing. Themouthpiece also includes a printed circuit board mounted to a bottomportion of the elongated housing, the printed circuit board having aplurality of electrodes for delivering subcutaneous local electricalstimulation to the patient's tongue. In some embodiments, the mouthpiecealso includes ribs aligned parallel to a longitudinal axis of theelongated housing. In some embodiments, the mouthpiece also includesribs aligned perpendicular to a longitudinal axis of the elongatedhousing. In some embodiments, the mouthpiece also includes ribs alignedparallel to a longitudinal axis of the elongated housing and ribsaligned perpendicular to a longitudinal axis of the elongated housing.In some embodiments, the mouthpiece also includes an interpenetratingnetwork of ribs, with at least some of the ribs aligned parallel to alongitudinal axis of the elongate housing and at least some of the ribsaligned perpendicular to a longitudinal axis of the elongated housing.In some embodiments, the mouthpiece also includes pockets in a posteriorportion of the elongated housing formed by the interpenetrating networkof ribs. In some embodiments, the mouthpiece also includes integratedcircuits located in the pockets. In some embodiments, the ribs have arectangular cross section. In some embodiments, the ribs are comprisedof arches. In some embodiments, the mouthpiece also includes one or morecolumns extending away from an interior surface of the elongatedhousing, the one or more columns configured to contact the mountedprinted circuit board. In some embodiments, the structural elements canwithstand a force of 700 Newtons without causing plastic deformation ofthe mouthpiece. In some embodiments, the mouthpiece also includes arectangular sheet embedded on an interior surface of the elongatedhousing and located in a posterior region of the elongated housing, therectangular sheet connecting the interpenetrating network of ribs. Insome embodiments, the mouthpiece also includes a curvilinear sheetembedded on an interior surface of the elongated housing and located ina region connecting the anterior region and the posterior region of theelongated housing, the curvilinear sheet connecting the ribs alignedparallel to a longitudinal axis of the elongated housing.

In another aspect, the invention features a mouthpiece for providingnon-invasive neuromodulation to a patient. The mouthpiece includes anelongated housing having an anterior region and a posterior region, theelongated housing having (i) a non-planar exterior top surface and (ii)internal structural members disposed within the housing, the internalstructural members elastically responding to biting forces generated bythe patient. The mouthpiece also includes a printed circuit boardmounted to a bottom portion of the elongated housing, the printedcircuit board having a plurality of electrodes for deliveringsubcutaneous local electrical stimulation to the patient's tongue. Insome embodiments, the mouthpiece also includes ribs aligned parallel toa longitudinal axis of the elongated housing. In some embodiments, themouthpiece also includes ribs aligned perpendicular to a longitudinalaxis of the elongated housing. In some embodiments, the mouthpiece alsoincludes ribs aligned parallel to a longitudinal axis of the elongatedhousing and ribs aligned perpendicular to a longitudinal axis of theelongated housing. In some embodiments, the mouthpiece also includes aninterpenetrating network of ribs, with at least some of the ribs alignedparallel to a longitudinal axis of the elongate housing and at leastsome of the ribs aligned perpendicular to a longitudinal axis of theelongated housing. In some embodiments, the mouthpiece also includespockets in a posterior portion of the elongated housing formed by theinterpenetrating network of ribs. In some embodiments, the mouthpiecealso includes integrated circuits located in the pockets. In someembodiments, the ribs have a rectangular cross section. In someembodiments, the ribs are comprised of arches. In some embodiments, themouthpiece also includes one or more columns extending away from aninterior surface of the elongated housing, the one or more columnsconfigured to contact the mounted printed circuit board. In someembodiments, the structural elements can withstand a force of 700Newtons without causing plastic deformation of the mouthpiece.

In another aspect, the invention features a mouthpiece for providingnon-invasive neuromodulation to a patient. The mouthpiece includes anelongated housing having an anterior region and a posterior region, theelongated housing having a non-planar interior top surface and internalfins located between the non-planar interior top surface and a bottomsurface defined by a perimeter of the elongated housing, the internalfins forming a channel at the anterior region of the elongated housing.The mouthpiece also includes a spacer attached to the top surface of thehousing for minimizing contact between a patient's upper teeth and theexterior top surface of the elongated housing. The mouthpiece alsoincludes a printed circuit board mounted to a bottom portion of theelongated housing, the printed circuit board having a plurality ofelectrodes for delivering subcutaneous local electrical stimulation tothe patient's tongue. The mouthpiece also includes a cable having afirst segment disposed within the housing and a second segment extendingfrom the housing, the cable mounted in an s-shaped pattern along thechannel formed by the internal fins, one end of the first segment of thecable connected to the printed circuit board. In some embodiments, themouthpiece also includes a right angled grommet mounted to an anteriorregion of the elongated housing, the grommet surrounding the cable as itexits the channel formed by the internal fins, the grommet forcing thecable to make an approximately ninety degree turn as it exits theelongated housing. In some embodiments, the cable forms two consecutives-shapes along the channel formed by the internal fins. In someembodiments, the mouthpiece also includes a grommet mounted to ananterior region of the elongated housing, the grommet surrounding thecable as it exits the channel formed by the internal fins. In someembodiments, the mouthpiece also includes a cylindrically symmetricelastomeric element, the elastomeric element surrounding a portion ofthe cable and having trench in a central portion thereof and surroundedby two regions having radii that decrease in relation to a distance fromthe trench. In some embodiments, the mouthpiece also includes anaperture located at an anterior region of the elongated housing, theaperture configured to form mechanical connection with the trench. Insome embodiments, the mouthpiece also includes a cap, the cap having anelastomeric portion in contact with the printed circuit board and arigid portion in contact with the elongated housing, the cap incooperation with the elongated housing forming an aperture at ananterior region of the mouthpiece, the aperture configured to formmechanical connection with the trench. In some embodiments, themouthpiece also includes a valley located in the interior surface of theelongated housing, the valley configured to receive the cable. In someembodiments, the mouthpiece also includes an elastomeric sleeve, theelastomeric sleeve in contact with the cable, and an anterior region ofthe elongated housing, the elastomeric sleeve providing resistance tobending and tensile strains in the cable.

In another aspect, the invention features a mouthpiece for providingnon-invasive neuromodulation to a patient. The mouthpiece includes anelongated housing having an anterior region and a posterior region, theelongated housing having a non-planar interior top surface and a bottomsurface defined by a perimeter of the elongated housing. The mouthpiecealso includes a spacer attached to the top surface of the elongatedhousing for minimizing contact between a patient's upper teeth and theexterior top surface of the elongated housing. The mouthpiece alsoincludes a printed circuit board mounted to a bottom portion of theelongated housing, the printed circuit board having a plurality ofelectrodes for delivering subcutaneous local electrical stimulation tothe patient's tongue. The mouthpiece also includes a first elastomericring located along an interior sidewall of the elongated housing, thefirst elastomeric ring forming a sealing surface with the printedcircuit board. The mouthpiece also includes a plurality of mechanicalprotrusions extending from the interior sidewall of the elongatedhousing, the mechanical protrusions in contact with the printed circuitboard. The mouthpiece also includes a cable having a first segmentdisposed within the housing and a second segment extending from thehousing, one end of the first segment of the cable connected to theprinted circuit board. In some embodiments, the mouthpiece also includesa valley located in the interior surface of the elongated housing, thevalley configured to receive the cable. In some embodiments, themouthpiece also includes internal fins extending from the interior topsurface of the elongated housing, the internal fins forming a channel atan anterior region of the elongated housing. In some embodiments, thecable forms at least two consecutive s-shapes along the channel formedby the internal fins. In some embodiments, the mouthpiece also includesa second elastomeric ring attached to the first elastomeric ring, thesecond elastomeric ring surrounding a portion of the cable and forming aconnection between an anterior portion of the elongated housing and thecable. In some embodiments, the mouthpiece also includes a secondelastomeric ring attached to the first elastomeric ring, the secondelastomeric ring surrounding a portion of the cable and forming aconnection between an anterior portion of the elongated housing and thecable, the second elastomeric ring causing the cable to exit themouthpiece at an angle of 90 degrees.

In another aspect, the invention features a mouthpiece for providingnon-invasive neuromodulation to a patient. The mouthpiece includes anelongated housing having an anterior region and a posterior region, theelongated housing having a non-planar interior top surface and internalfins located between the non-planar interior top surface and a bottomsurface defined by a perimeter of the elongated housing, the internalfins forming a channel at the anterior region of the elongated housing.The mouthpiece also includes a printed circuit board mounted to a bottomportion of the elongated housing, the printed circuit board having aplurality of electrodes for delivering subcutaneous local electricalstimulation to the patient's tongue. The mouthpiece also includes acable having a first segment disposed within the housing and a secondsegment extending from the housing, the cable mounted in an s-shapedpattern along the channel formed by the internal fins, one end of thefirst segment of the cable connected to the printed circuit board. Insome embodiments, the mouthpiece also includes a right angled grommetmounted to an anterior region of the elongated housing, the grommetsurrounding the cable as it exits the channel formed by the internalfins, the grommet forcing the cable to make an approximately ninetydegree turn as it exits the elongated housing. In some embodiments, thecable forms two consecutive s-shapes along the channel formed by theinternal fins. In some embodiments, the mouthpiece also includes agrommet mounted to an anterior region of the elongated housing, thegrommet surrounding the cable as it exits the channel formed by theinternal fins. In some embodiments, the mouthpiece also includes acylindrically symmetric elastomeric element, the elastomeric elementsurrounding a portion of the cable and having trench in a centralportion thereof and surrounded by two regions having radii that decreasein relation to a distance from the trench. In some embodiments, themouthpiece also includes an aperture located at an anterior region ofthe elongated housing, the aperture configured to form mechanicalconnection with the trench. In some embodiments, the mouthpiece alsoincludes a cap, the cap having an elastomeric portion in contact withthe printed circuit board and a rigid portion in contact with theelongated housing, the cap in cooperation with the elongated housingforming an aperture at an anterior region of the mouthpiece, theaperture configured to form mechanical connection with the trench. Insome embodiments, the mouthpiece also includes a valley located in theinterior surface of the elongated housing, the valley configured toreceive the cable. In some embodiments, the mouthpiece also includes anelastomeric sleeve, the elastomeric sleeve in contact with the cable,and an anterior region of the elongated housing, the elastomeric sleeveproviding resistance to bending and tensile strains in the cable.

In another aspect, the invention features a mouthpiece for providingnon-invasive neuromodulation to a patient. The mouthpiece includes anelongated housing having an anterior region and a posterior region, theelongated housing having a non-planar exterior top surface. Themouthpiece also includes a spacer attached to the top surface of thehousing for minimizing contact between a patient's upper teeth and theexterior top surface of the elongated housing. The mouthpiece alsoincludes a first printed circuit board mounted to a bottom portion ofthe elongated housing, the first printed circuit board having aplurality of electrodes for delivering subcutaneous local electricalstimulation to the patient's tongue. The mouthpiece also includes a rimextending from a bottom portion of the elongated housing, the rimsurrounding a perimeter of the first printed circuit board and having au-shaped cross section. The mouthpiece also includes a well shaped toaccommodate an adhesive, the adhesive bonding the first printed circuitboard to the elongate housing. In some embodiments, a portion of the rimrests below the first printed circuit board and prevents a patient'steeth from contacting the printed circuit board. In some embodiments,the first printed circuit board is non-planar and the plurality ofelectrodes are located on a non-planar surface of the first printedcircuit board. In some embodiments, the first printed circuit board hasa curved shape and the plurality of electrodes are located on a curvedsurface of the first printed circuit board. In some embodiments, theplurality of electrodes has a first density at an anterior region of thefirst printed circuit board and a second density at a posterior regionof the first printed circuit board, wherein the first density is greaterthan the second density. In some embodiments, the mouthpiece alsoincludes a second printed circuit board mounted above the first printedcircuit board. In some embodiments, the rim is an integral part of theelongated housing. In some embodiments, the rim is dimensioned to definethe glue well between the bottom portion of the elongated housing andthe perimeter of the first printed circuit board. In some embodiments,the rim is concentric with the perimeter of the first printed circuitboard. In some embodiments, the rim covers a bottom portion of the firstprinted circuit board along the perimeter thereof. In some embodiments,the rim covers a side portion of the first printed circuit board alongthe perimeter thereof. In some embodiments, the rim covers a bottomportion and a side portion of the first printed circuit board along theperimeter thereof.

In another aspect, the invention features a mouthpiece for providingnon-invasive neuromodulation to a patient. The mouthpiece includes anelongated housing having an anterior region and a posterior region, theelongated housing having a non-planar exterior top surface. Themouthpiece also includes a spacer attached to the top surface of thehousing for minimizing contact between a patient's upper teeth and theexterior top surface of the elongated housing. The mouthpiece alsoincludes a first printed circuit board mounted to a bottom portion ofthe elongated housing, the first printed circuit board having aplurality of electrodes for delivering subcutaneous local electricalstimulation to the patient's tongue. The mouthpiece also includes a rimextending from a bottom portion of the elongated housing, the rimsurrounding a perimeter of the first printed circuit board. Themouthpiece also includes a beveled well configured to accommodate anadhesive, the adhesive bonding at least two orthogonal surfaces of thefirst printed circuit board to the elongated housing. In someembodiments, a portion of the rim rests below the first printed circuitboard and prevents a patient's teeth from contacting the first printedcircuit board. In some embodiments, the first printed circuit board isnon-planar and the plurality of electrodes are located on a non-planarsurface of the first printed circuit board. In some embodiments, thefirst printed circuit board has a curved shape and the plurality ofelectrodes are located on a curved surface of the first printed circuitboard. In some embodiments, the plurality of electrodes has a firstdensity at an anterior region of the first printed circuit board and asecond density at a posterior region of the first printed circuit board,wherein the first density is greater than the second density. In someembodiments, the mouthpiece also includes a second printed circuit boardmounted above the first printed circuit board. In some embodiments, therim is an integral part of the elongated housing. In some embodiments,the rim is dimensioned to define the glue well between the bottomportion of the elongated housing and the perimeter of the first printedcircuit board. In some embodiments, the rim is concentric with theperimeter of the first printed circuit board. In some embodiments, therim covers a bottom portion of the first printed circuit board along theperimeter thereof. In some embodiments, the rim covers a side portion ofthe first printed circuit board along the perimeter thereof. In someembodiments, the rim covers a bottom portion and a side portion of thefirst printed circuit board along the perimeter thereof.

In another aspect, the invention features a method of manufacturing amouthpiece, the mouthpiece providing non-invasive neuromodulation to apatient. The method includes providing an elongated housing havinginternal fins located between a non-planar interior top surface and abottom surface defined by a perimeter of the elongated housing, theinternal fins forming a channel at the anterior region of the elongatedhousing. The method also includes attaching a spacer to the top surfaceof the elongated housing for minimizing contact between a patient'supper teeth and the exterior top surface of the elongated housing. Themethod also includes mounting a cable in an s-shaped pattern along thechannel formed by the internal fins. The method also includes mounting aprinted circuit board to a bottom portion of the elongated housing, theprinted circuit board having a plurality of electrodes for deliveringsubcutaneous local electrical stimulation to the patient's tongue. Themethod also includes connecting one end of the cable to the printedcircuit board. In some embodiments, the method also includes forming a90 degree bend in the cable at an exit of elongated housing. In someembodiments, the method also includes threading the cable through anelastomeric element located at the exit of the elongated housing. Insome embodiments, the method also includes forming two consecutives-shapes along the cable. In some embodiments, the method also includesmounting a cylindrically symmetric elastomeric element to the cable, theelastomeric element surrounding a portion of the cable and having atrench in a central portion thereof and surrounded by two regions havingradii that decrease in relation to a distance from the trench. In someembodiments, the method also includes forming an aperture at an anteriorregion of the elongated housing, the aperture configured to formmechanical connection with the trench. In some embodiments, the methodalso includes providing a cap having an elastomeric portion and a rigidportion. In some embodiments, the method also includes contacting theelastomeric portion of the cap with the printed circuit board andcontacting the rigid portion of the cap with the elongated housing. Insome embodiments, the method also includes cooperatively forming anaperture with the cap and the elongated housing, the aperture forming amechanical connection with the trench. In some embodiments, the methodalso includes forming a valley located in the interior surface of theelongated housing. In some embodiments, the method also includesreceiving a cable in the valley. In some embodiments, the method alsoincludes forming an elastomeric sleeve around the cable, the elastomericsleeve in contact with an anterior region of the elongated housing, theelastomeric sleeve providing resistance to bending and tensile strainsin the cable. In some embodiments, the method also includes applying anadhesive along the perimeter of the printed circuit board, the adhesivebonding at least two orthogonal surfaces of the first printed circuitboard to the elongated housing.

In another aspect, the invention features a method of manufacturing amouthpiece, the mouthpiece providing non-invasive neuromodulation to apatient. The method includes providing an elongated housing having aplurality of mechanical protrusions extending from an interior sidewallthereof and first elastomeric ring located along an interior sidewall ofthe elongated housing. The method also includes attaching a spacer tothe top surface of the elongated housing for minimizing contact betweena patient's upper teeth and a top surface of the elongated housing. Themethod also includes contacting a printed circuit board to the firstelastomeric ring of the elongated housing to form a seal, the printedcircuit board having a plurality of electrodes for deliveringsubcutaneous local electrical stimulation to the patient's tongue. Themethod also includes providing a cable having a first segment disposedwithin the housing and a second segment extending from the housing. Themethod also includes connecting one end of the first segment of thecable connected to the printed circuit board. In some embodiments, themethod also includes forming a 90 degree bend in the cable at an exit ofelongated housing. In some embodiments, the method also includesthreading the cable through an elastomeric element located at the exitof the elongated housing. In some embodiments, the method also includesforming two consecutive s-shapes along the cable. In some embodiments,the method also includes mounting a cylindrically symmetric elastomericelement to the cable, the elastomeric element surrounding a portion ofthe cable and having a trench in a central portion thereof andsurrounded by two regions having radii that decrease in relation to adistance from the trench. In some embodiments, the method also includesforming an aperture at an anterior region of the elongated housing, theaperture configured to form mechanical connection with the trench. Insome embodiments, the method also includes forming a valley located inthe interior surface of the elongated housing. In some embodiments, themethod also includes receiving a cable in the valley. In someembodiments, the method also includes forming an elastomeric sleevearound the cable, the elastomeric sleeve in contact with an anteriorregion of the elongated housing, the elastomeric sleeve providingresistance to bending and tensile strains in the cable.

In another aspect, the invention features a method of manufacturing amouthpiece, the mouthpiece providing non-invasive neuromodulation to apatient. The method includes providing a printed circuit board, theprinted circuit board having electronic circuitry and a plurality ofelectrodes for delivering subcutaneous local electrical stimulation tothe patient's tongue. The method also includes forming an elongatedhousing directly onto the printed circuit board. The method alsoincludes attaching a spacer to the top surface of the elongated housingfor minimizing contact between a patient's upper teeth and a top surfaceof the elongated housing.

In some embodiments, the method also includes forming a strain reliefmechanism integral with the elongated housing. In some embodiments, themethod also includes providing a cable having a first segment disposedwithin the housing and a second segment extending from the housing. Insome embodiments, the method also includes connecting one end of thefirst segment of the cable connected to the printed circuit board. Insome embodiments, the method also includes encapsulating the electroniccircuitry located on the printed circuit board.

As used herein, the terms “approximately,” “roughly,” and“substantially” mean±10%, and in some embodiments, ±5%. Referencethroughout this specification to “one example,” “an example,” “oneembodiment,” or “an embodiment” means that a particular feature,structure, or characteristic described in connection with the example isincluded in at least one example of the present technology. Thus, theoccurrences of the phrases “in one example,” “in an example,” “oneembodiment,” or “an embodiment” in various places throughout thisspecification are not necessarily all referring to the same example.Furthermore, the particular features, structures, routines, steps, orcharacteristics may be combined in any suitable manner in one or moreexamples of the technology. The headings provided herein are forconvenience only and are not intended to limit or interpret the scope ormeaning of the claimed technology.

BRIEF DESCRIPTION OF THE DRAWINGS

The advantages of the invention described above, together with furtheradvantages, may be better understood by referring to the followingdescription taken in conjunction with the accompanying drawings. Thedrawings are not necessarily to scale, emphasis instead generally beingplaced upon illustrating the principles of the invention.

FIG. 1 is a drawing of a patient engaged in a non-invasiveneurostimulation therapy session according to an illustrative embodimentof the invention.

FIGS. 2A and 2B are diagrams showing a neurostimulation system accordingto an illustrative embodiment of the invention.

FIG. 2C is a diagram showing a neurostimulation system according to anillustrative embodiment of the invention.

FIG. 3A is a diagram showing a more detailed view of theneurostimulation system depicted in FIGS. 2A and 2B.

FIG. 3B is a diagram showing a more detailed view of theneurostimulation system depicted in FIG. 2C.

FIG. 3C is a diagram showing a more detailed view of an electrode array.

FIG. 3D is a graph showing an exemplary sequence of pulses for effectingneurostimulation of a patient.

FIG. 4A is a flow chart illustrating a method in accordance with oneembodiment for operating a neurostimulation system.

FIG. 4B is a flow chart illustrating a method in accordance with oneembodiment for operating a neurostimulation system.

FIG. 5A is a diagram showing an isometric view of a mouthpiece inaccordance with an illustrative embodiment of the invention.

FIG. 5B is a diagram showing a side view of a mouthpiece in accordancewith an illustrative embodiment of the invention.

FIG. 5C is a diagram showing a top view of a mouthpiece in accordancewith an illustrative embodiment of the invention.

FIG. 5D is a diagram showing a bottom view of a mouthpiece in accordancewith an illustrative embodiment of the invention.

FIGS. 5E and 5F are diagrams showing a bottom view of the mouthpiece inaccordance with an illustrative embodiment of the invention.

FIG. 6A is a diagram showing an isometric view of a mouthpiece inaccordance with an illustrative embodiment of the invention.

FIG. 6B is a diagram showing a bottom view of the mouthpiece inaccordance with an illustrative embodiment of the invention.

FIG. 6C is a diagram showing a glue well in accordance with anillustrative embodiment of the invention.

FIG. 6D is a diagram showing a glue well in accordance with anillustrative embodiment of the invention.

FIG. 7A is a diagram showing an isometric view of a mouthpiece inaccordance with an illustrative embodiment of the invention.

FIG. 7B is a diagram showing a bottom view of the mouthpiece inaccordance with an illustrative embodiment of the invention.

FIG. 7C is a diagram showing a sectional view of the mouthpiece inaccordance with an illustrative embodiment of the invention.

FIGS. 8A and 8B are diagrams showing an isometric view of a mouthpiecein accordance with an illustrative embodiment of the invention.

FIG. 8C is a diagram showing a sectional view of the mouthpiece inaccordance with an illustrative embodiment of the invention.

FIG. 8D is a diagram showing a sectional view of the mouthpiece inaccordance with an illustrative embodiment of the invention.

FIGS. 9A and 9B are diagrams showing an isometric view of a mouthpiecein accordance with an illustrative embodiment of the invention.

FIG. 9C is a diagram showing a sectional view of the mouthpiece inaccordance with an illustrative embodiment of the invention.

FIGS. 10A and 10B are diagrams showing an isometric view of a mouthpiecein accordance with an illustrative embodiment of the invention.

FIG. 10C is a diagram showing a sectional view of the mouthpiece inaccordance with an illustrative embodiment of the invention.

FIGS. 11A and 11B are diagrams showing an isometric view of a mouthpiecein accordance with an illustrative embodiment of the invention.

FIG. 11C is a diagram showing an isometric view of the mouthpiece inaccordance with an illustrative embodiment of the invention.

FIG. 12 is a flow chart illustrating a method in accordance with oneembodiment for manufacturing a mouthpiece.

FIGS. 13A-B are diagrams showing an overmolded mouthpiece in accordancewith an illustrative embodiment of the invention.

FIG. 14 is a diagram showing an overmolded mouthpiece in accordance withan illustrative embodiment of the invention.

DETAILED DESCRIPTION

FIG. 1 shows a patient 101 undergoing non-invasive neuromodulationtherapy (NINM) using a neurostimulation system 100. During a therapysession, the neurostimulation system 100 non-invasively stimulatesvarious nerves located within the patient's oral cavity, including atleast one of the trigeminal and facial nerves. In combination with theNINM, the patient engages in an exercise or other activity specificallydesigned to assist in the neurorehabilitation of the patient. Forexample, the patient can perform a physical therapy routine (e.g.,moving an affected limb, or walking on a treadmill) engage in a mentaltherapy (e.g., meditation or breathing exercises), or a cognitiveexercise (e.g., computer assisted memory exercises) during theapplication of NINM. The combination of NINM with an appropriatelychosen exercise or activity has been shown to be useful in treating arange of maladies including, for example, traumatic brain injury, stroke(TBI), multiple sclerosis (MS), balance, gait, vestibular disorders,visual deficiencies, tremor, headache, migraines, neuropathic pain,hearing loss, speech recognition, auditory problems, speech therapy,cerebral palsy, blood pressure, relaxation, and heart rate. For example,a useful non-invasive neuromodulation (NINM) therapy routine has beenrecently developed as described in U.S. Pat. No. 8,849,407, the entiretyof which is incorporated herein by reference.

FIGS. 2A and 2B show a non-invasive neurostimulation system 100. Thenon-invasive neurostimulation system 100 includes a controller 120 and amouthpiece 140. The controller 120 includes a receptacle 126 andpushbuttons 122. The mouthpiece 140 includes an electrode array 142 anda cable 144. The cable 144 connects to the receptacle 126, providing anelectrical connection between the mouthpiece 140 and the controller 120.In some embodiments, the controller 120 includes a cable. In someembodiments, the mouthpiece 140 and the controller 120 are connectedwirelessly (e.g., without the use of a cable). During operation, apatient activates the neurostimulation system 100 by actuating one ofthe pushbuttons 122. In some embodiments, the neurostimulation system100 periodically transmits electrical pulses to determine if theelectrode array 142 is in contact with the patient's tongue andautomatically activates based on the determination. After activation,the patient can start an NINM treatment session, stop the NINM treatmentsession, or pause the NINM treatment session by pressing one of thepushbuttons 122. In some embodiments, the neurostimulation system 100periodically transmits electrical pulses to determine if the electrodearray 142 is in contact with the patient's tongue and automaticallypauses the NINM treatment session based on the determination. During anNINM treatment session, the patient engages in an exercise or otheractivity designed to facilitate neurorehabilitation. For example, duringan NINM treatment session, the patient can engage in a physicalexercise, a mental exercise, or a cognitive exercise. In someembodiments, the controller 120 has pushbuttons on both arms. In someembodiments, a mobile device can be used in conjunction with thecontroller 120 and the mouthpiece 140. The mobile device can include asoftware application that allows a user to activate the neurostimulationsystem 100 and start or stop an NINM treatment session by for example,pressing a button on the mobile device, or speaking a command into themobile device. The mobile device can obtain patient information andtreatment session information before, during, or after an NINM treatmentsession. In some embodiments, the controller 120 includes a securecryptoprocessor that holds a secret key, to be described in more detailbelow in connection with FIGS. 9A and 9B. The secure cryptoprocessor isin communication with a microcontroller. The secure cryptoprocessor canbe tamper proof. For example, if outer portions of the cryptoprocessorare removed in an attempt to access the secret key, the cryptoprocessorerases all memory, preventing unauthorized access of the secret key.

FIG. 2C shows a non-invasive neurostimulation system 100. As shown, amobile device 121 is in communication with a mouthpiece 140. Morespecifically, the mobile device 121 includes a processor running asoftware application that facilitates communications with the mouthpiece140. The mobile device 121 can be, for example, a mobile phone, aportable digital assistant (PDA), or a laptop. The mobile device 121 cancommunicate with the mouthpiece 140 by a wireless or wired connection.During operation, a patient activates the neurostimulation system 100via the mobile device 121. After activation, the patient can start anNINM treatment session, stop the NINM treatment session, or pause theNINM treatment session by manipulating the mobile device 121. During anNINM treatment session, the patient engages in an exercise or activitydesigned to provide neurorehabilitation. For example, during an NINMtreatment session, the patient can engage in a physical exercise, amental exercise, or a cognitive exercise.

FIG. 3A shows the internal circuitry housed within the controller 120.The circuitry includes a microcontroller 360, isolation circuitry 379, auniversal serial bus (USB) connection 380, a battery managementcontroller 382, a battery 362, a push-button interface 364, a display366, a real time clock 368, an accelerometer 370, drive circuitry 372,tongue sense circuitry 374, audio feedback circuitry 376, vibratoryfeedback circuitry 377, and a non-volatile memory 378. The drivecircuitry 372 includes a multiplexor, and an array of resistors tocontrol voltages delivered to the electrode array 142. Themicrocontroller 360 is in electrical communication with each of thecomponents shown in FIG. 3A. The isolation circuitry 379 provideselectrical isolation between the USB connection 380 and all othercomponents included in the controller 120. Additionally, the circuitryshown in FIG. 3A is in communication with the mouthpiece 140 via theexternal cable 144. During operation, the microcontroller 360 receiveselectrical power from battery 362 and can store and retrieve informationfrom the non-volatile memory 378. The battery can be charged via the USBconnection 380. The battery management circuitry controls the chargingof the battery 362. A patient can interact with the controller 120 viathe push-button interface 122 that converts the patient's pressing of abutton (e.g. an info button, a power button, an intensity-up button, anintensity-down button, and a start/stop button) into an electricalsignal that is transmitted to the microcontroller 360. For example, atherapy session can be started when the patient presses a start/stopbutton after powering on the controller 120. During the therapy session,the drive circuitry 372 provides an electrical signal to the mouthpiece140 via the cable 144. The electrical signal is communicated to thepatient's intraoral cavity via the electrode array 142. Theaccelerometer 370 can be used to provide information about the patient'smotion during the therapy session. Information provided by theaccelerometer 370 can be stored in the non-volatile memory 378 at acoarse or detailed level. For example, a therapy session aggregatemotion index can be stored based on the number of instances whereacceleration rises above a predefined threshold, with or without lowpass filtering. Alternatively, acceleration readings could be stored ata predefined sampling interval. The information provided by theaccelerometer 370 can be used to determine if the patient is engaged ina physical activity. Based on the information received from theaccelerometer 370, the microcontroller 360 can determine an activitylevel of the patient during a therapy session. For example, if thepatient engages in a physical activity for 30 minutes during a therapysession, the accelerometer 370 can periodically communicate (e.g. onceevery second) to the microcontroller 360 that the sensed motion islarger than a predetermined threshold (e.g. greater than 1 m/s²). Insome embodiments, the accelerometer data is stored in the non-volatilememory 378 during the therapy session and transmitted to the mobiledevice 121 after the therapy session has ended. After the therapysession has ended, the microcontroller 360 can record the amount of timeduring the therapy session in which the patient was active. In someembodiments, the recorded information can include other data about thetherapy session (e.g., the date and time of the session start, theaverage intensity of electrical neurostimulation delivered to thepatient during the session, the average activity level of the patientduring the session, the total session time the mouthpiece has been inthe patient's mouth, the total session pause time, the number of sessionshorting events, and/or the length of the session or the type ofexercise or activity performed during the therapy session) and can betransmitted to a mobile device. A session shorting event can occur ifthe current transmitted from the drive circuitry to the electrode array142 exceeds a predetermined threshold or if the charge transmitted fromthe drive circuitry to the electrode array exceeds a predeterminedthreshold over a predetermined time interval. After a session shortingevent has occurred, the patient must manually press a pushbutton toresume the therapy session. The real time clock (RTC) 368 provides timeand date information to the microcontroller 360. In some embodiments,the controller 120 is authorized by a physician for a predeterminedperiod of time (e.g., two weeks). The RTC 368 periodically communicatesdate and time information to the microcontroller 360. In someembodiments, the RTC 368 is integrated with the microcontroller. In someembodiments, the RTC 368 is powered by the battery 362, and upon failureof the battery 362, the RTC 368 is powered by a backup battery. Afterthe predetermined period of time has elapsed, the controller 120 can nolonger initiate the delivery of electrical signals to the mouthpiece 140and the patient must visit the physician to reauthorize use of thecontroller 120. The display 366 displays information received by themicrocontroller 360 to the patient. For example, the display 366 candisplay the time of day, therapy information, battery information, timeremaining in a therapy session, error information, and the status of thecontroller 120. The audio feedback circuitry 376 and vibratory feedbackcircuitry 377 can give feedback to a user when the device changes state.For example, when a therapy session begins, the audio feedback circuitry376 and the vibratory feedback circuitry 377 can provide auditory and/orvibratory cues to the patient, notifying the patient that the therapysession has been initiated. Other possible state changes that maytrigger audio and/or vibratory cues include pausing a therapy session,resuming a therapy session, the end of a timed session, canceling atimed session, or error messaging. In some embodiments, a clinician canturn off one or more of the auditory or vibratory cues to tailor thefeedback to an individual patient's needs. The tongue sense circuitry374 measures the current passing from the drive circuitry to theelectrode array 142. Upon sensing a current above a predeterminedthreshold, the tongue sense circuitry 374 presents a high digital signalto the microcontroller 360, indicating that the tongue is in contactwith the electrode array 142. If the current is below the predeterminedthreshold, the tongue sense circuitry 374 presents a low digital signalto the microcontroller 360, indicating that the tongue is not in contactor is in partial contact with the electrode array 142. The indicationsreceived from the tongue sense circuitry 374 can be stored in thenon-volatile memory 378. In some embodiments, the display 366 can be anorganic light emitting diode (OLED) display. In some embodiments, thedisplay 366 can be a liquid crystal display (LCD). In some embodiments,a display 366 is not included with the controller 120. In someembodiments, neither the controller 120 nor the mouthpiece 140 includesa cable, and the controller 120 communicates wirelessly with themouthpiece 140. In some embodiments, neither the controller 120 nor themouthpiece 140 includes an accelerometer. In some embodiments, the drivecircuitry 372 is located within the mouthpiece. In some embodiments, aportion of the drive circuitry 372 is located within the mouthpiece 140and a portion of the drive circuitry 372 is located within thecontroller 120. In some embodiments, neither the controller 120 nor themouthpiece 140 includes tongue sense circuitry 374. In some embodiments,the mouthpiece 140 includes a microcontroller and a multiplexer.

FIG. 3B shows a more detailed view of FIG. 2C. The mouthpiece 140includes a battery 362, tongue sense circuitry 374, an accelerometer370, a microcontroller 360, drive circuitry 372, a non-volatile memory378, a universal serial bus controller (USB) 380, and battery managementcircuitry 382. During operation, the microcontroller receives electricalpower from battery 362 and can store and retrieve information from thenon-volatile memory 378. The battery can be charged via the USBconnection 380. The battery management circuitry 382 controls thecharging of the battery 362. A patient can interact with the mouthpiece140 via the mobile device 121. The mobile device 121 includes anapplication (e.g. software running on a processor) that allows thepatient to control the mouthpiece 140. For example, the application caninclude an info button, a power button an intensity-up button, anintensity-down button, and a start/stop button that are presented to theuser visually via the mobile device 121. When the patient presses abutton presented by the application running on the mobile device 121, asignal is transmitted to the microcontroller 360 housed within themouthpiece 140. For example, a therapy session can be started when thepatient presses a start/stop button on the mobile device 121. During thetherapy session, the drive circuitry 372 provides an electrical signalto an electrode array 142 located on the mouthpiece 140. Theaccelerometer 370 can be used to provide information about the patient'smotion during the therapy session. The information provided by theaccelerometer 370 can be used to determine if the patient is engaged ina physical activity. Based on the information received from theaccelerometer 370, the microcontroller 360 can determine an activitylevel of the patient during a therapy session. For example, if thepatient engages in a physical activity for 30 minutes during a therapysession, the accelerometer 370 can periodically communicate (e.g. onceevery second) to the microcontroller 360 that the sensed motion islarger than a predetermined threshold (e.g. greater than 1 m/s²). Afterthe therapy session has ended, the microcontroller 360 can record theamount of time during the therapy session in which the patient wasactive. In some embodiments, the accelerometer 370 is located within themobile device 121 and the mobile device 121 determines an activity levelof a patient during the therapy session based on information receivedfrom the accelerometer 370. The mobile device can then record the amountof time during the therapy session in which the patient was active. Themobile device 121 includes a real time clock (RTC) 368 that providestime and date information to the microcontroller 360. In someembodiments, the mouthpiece 140 is authorized by a physician for apredetermined period of time (e.g., two weeks). After the predeterminedperiod of time has elapsed, the mouthpiece 140 can no longer deliverelectrical signals to the patient via the electrode array 142 and thepatient must visit the physician to reauthorize use of the mouthpiece140. In some embodiments, the mouthpiece 140 includes pushbuttons (e.g.,an on/off button) and a patient can manually operate the mouthpiece 140via the pushbuttons. After a therapy session, the mouthpiece 140 cantransmit information about the therapy session to a mobile device. Insome embodiments, the mouthpiece 140 does not include a USB controller380 and instead communicates only via wireless communications with thecontroller.

FIG. 3C shows a more detailed view of the electrode array 142. Theelectrode array 142 can be separated into 9 groups of electrodes,labelled a-i, with each group having 16 electrodes, except group b whichhas 15 electrodes. Each electrode within the group corresponds to one of16 electrical channels. During operation, the drive circuitry candeliver a sequence of electrical pulses to the electrode array 142 toprovide neurostimulation of at least one of the patient's trigeminal orfacial nerve. The electrical pulse amplitude delivered to each group ofelectrodes can be larger near a posterior portion of the tongue andsmaller at an anterior portion of the tongue. For example, the pulseamplitude of electrical signals delivered to groups a-c can be 19 voltsor 100% of a maximum value, the pulse amplitude of electrical signalsdelivered to groups d-f can be 14.25 volts or 75% of the maximum value,the pulse amplitude of electrical signals delivered to groups g-h can be11.4 volts or 60% of the maximum value, and the pulse amplitude ofelectrical signals delivered to group i can be 9.025 volts or 47.5% ofthe maximum value. In some embodiments, the maximum voltage is in therange of 0 to 40 volts. The pulses delivered to the patient by theelectrode array 142 can be random or repeating. The location of pulsescan be varied across the electrode array 142 such that differentelectrodes are active at different times, and the duration and/orintensity of pulses may vary from electrode. For oral tissuestimulation, currents of 0.5-50 mA and voltages of 1-40 volts can beused. In some embodiments, transient currents can be larger than 50 mA.The stimulus waveform may have a variety of time-dependent forms, andfor cutaneous electrical stimulation, pulse trains and bursts of pulsescan be used. Where continuously supplied, pulses may be 1-500microseconds long and repeat at rates from 1-1000 pulses/second. Wheresupplied in bursts, pulses may be grouped into bursts of 1-100pulses/burst, with a burst rate of 1-100 bursts/second.

In some embodiments, pulsed waveforms are delivered to the electrodearray 142. FIG. 3D shows an exemplary sequence of pulses that can bedelivered to the electrode array 142 by the drive circuitry 372. A burstof three pulses, each spaced apart by 5 ms is delivered to each of the16 channels. The pulses in neighboring channels are offset from oneanother by 312.5 μs. The burst of pulses repeats every 20 ms. The widthof each pulse can be varied from 0.3-60 μs to control an intensity ofneurostimulation (e.g., a pulse having a width of 0.3 μs will cause asmaller amount of neurostimulation than a pulse having a width of 60μs).

FIG. 4A shows a method of operation 400 of a controller 120 as describedin FIGS. 2A, 2B and 3A. A patient attaches a mouthpiece 140 to acontroller 120 (step 404). The patient turns on the controller 120 (step408) using, for example, a power button. The patient places thecontroller 120 around his/her neck (step 412) as shown in FIG. 1B. Thepatient places a mouthpiece 140 in his/her mouth (step 416). The patientinitiates a therapy session by pressing a start/stop button (step 420).During the therapy session, the controller 120 delivers electricalsignals to the mouthpiece 140. The patient calibrates the intensity ofthe electrical signals (step 424). The patient raises the intensity ofthe electrical signals delivered to the mouthpiece by pressing anintensity-up button until the neurostimulation is above the patient'ssensitivity level. The patient presses an intensity-down button untilthe neurostimulation is comfortable and non-painful. After thecalibration step, the patient performs a prescribed exercise (step 428).The exercise can be cognitive, mental, or physical. In some embodiments,physical exercise includes the patient attempting to maintain a normalposture or gait, the patient moving his/her limbs, or the patientundergoing speech exercises. Cognitive exercises can include “braintraining” exercises, typically computerized, that are designed torequire the use of attention span, memory, or reading comprehension.Mental exercises can include visualization exercises, meditation,relaxation techniques, and progressive exposure to “triggers” forcompulsive behaviors.

In some embodiments, the patient can rest for a period of time duringthe therapy session (e.g. the patient can rest for 2 minutes during a 30minute therapy session). After a predetermined period of time (forexample, thirty minutes) has elapsed, the therapy session ends (step432) and the controller 120 stops delivering electrical signals to themouthpiece 140. In some embodiments, the intensity of electrical signalsincreases from zero to the last use level selected by the patient over atime duration in the range of 1-5 seconds after the patient starts atherapy session by pressing the start/stop button. In some embodiments,the intensity of electrical signals is set to a fraction of the last uselevel selected by the patient (e.g. ¾ of the last level selected) afterthe patient starts a therapy session by pressing the start/stop button.In some embodiments, the intensity of electrical signals increases fromzero to a fraction of the last use level selected by the patient (e.g. ¾of the last level selected) over a time duration in the range of 1-5seconds after the patient starts a therapy session by pressing thestart/stop button. In some embodiments, the intensity of electricalsignals increases instantaneously from zero to the last use levelselected by the patient after the patient starts a therapy session bypressing the start/stop button.

In some embodiments, the mouthpiece 140 is connected to the controller120 after the controller 120 is turned on. In some embodiments, themouthpiece 140 is connected to the controller 120 after the controller120 is donned by the patient. In some embodiments, the patientcalibrates the intensity of the electrical signals before initiating atherapy session. In some embodiments, a patient performs an initialcalibration of the intensity of electrical signals in the presence of aclinician and does not calibrate the intensity of the electrical signalsduring subsequent treatments performed in the absence of a clinician.

FIG. 4B shows a method of operation 449 of the non-invasiveneurostimulation system 100 described in FIGS. 2C and 3B. A patientactivates a mobile device 121 (step 450). The patient places amouthpiece 140 in his/her mouth (step 454). The patient initiates atherapy session by pressing a start/stop button within an applicationrunning on the mobile device 121 (step 458). During the therapy session,circuitry within the mouthpiece 140 delivers electrical signals to anelectrode array 142 located on the mouthpiece 140. The patientcalibrates the intensity of the electrical signals (step 462). Thepatient first raises the intensity of the electrical signals deliveredto the mouthpiece 140 by pressing an intensity-up button located withinan application running on the mobile device 121 until theneurostimulation is above the patient's sensitivity level. The patientpresses an intensity-down button running within an application on themobile device 121 until the neurostimulation is comfortable andnon-painful. After the calibration step, the patient performs aprescribed exercise (step 464). The exercise can be cognitive, mental,or physical. In some embodiments, the patient can rest for a period oftime during the therapy session (e.g. the patient can rest for 5 minutesduring a 30 minute therapy session). After a predetermined period oftime (for example, thirty minutes) has elapsed, the therapy session ends(step 468) and the circuitry located within the mouthpiece 140 stopsdelivering electrical signals to the electrode array 142. In someembodiments, the calibration of the intensity of the electrical signalstakes place before the patient initiates a therapy session.

FIGS. 5A-5F show a mouthpiece 500. The mouthpiece 500 includes a housing504, a spacer 508, a transition region 520, a posterior region 524, ananterior region 528, a printed circuit board 532, internal circuitry533, an electrode array 542, and a cable 544. The housing 504 includesan outer shell 505, longitudinal ribs 550, transverse ribs 551, columns552, valleys 553, shoring 554, pockets 555, and a platform 558. Themouthpiece 500 has three regions, a posterior region 524, a transitionregion 520, and an anterior region 528. The transition region 520smoothly connects the anterior region 528 with the posterior region 524.The printed circuit board 532 attaches to the bottom side of the housing504. The internal circuitry 533 is mounted to the top side of theprinted circuit board 532 and is covered by the housing 504. The cable544 is in communication with the internal circuitry 533 and the internalcircuitry 533 is in communication with the electrode array 542. Theouter shell 505 of the housing 504 has an exemplary thickness in therange of 0.5 to 2 mm. The outer shell can be made of glass filled nylon,nylon, acrylonitrile butadiene styrene (ABS), polycarbonate (PC),polyether ether ketone (PEEK), alloy metal, or metal, having acompression strength in the range of 375 to 590N. In some embodiments,the outer shell 505 has two different thicknesses. For example, theanterior region of the outer shell 505 can have a thickness in the rangeof 1.2 to 2 mm and the posterior region can have a thickness in therange of 0.5 to 1.2 mm. The thickness of the outer shell 505 can varysmoothly in the transition region such that there are no discontinuitiesor steps in the thickness of the outer shell 505. In some embodiments,the thickness of the outer shell 505 in the anterior region is chosen towithstand biting by the patient. In some embodiments, the thickness ofthe outer shell 505 in the posterior region is selected to provideretention of the mouthpiece 500, thereby preventing accidental ejectionof the mouthpiece 500. By itself, the outer shell 505 cannot withstandbiting forces from the patient (e.g., the outer shell undergoessignificant deflections and/or experiences plastic deformation). Thelongitudinal ribs 550, transverse ribs 551, columns 552, shoring 554,and platform 558 can provide structural support for the outer shell 505to prevent damage due to biting by the patient. The longitudinal ribs550 can extend longitudinally along the housing 504. The longitudinalribs 550 can be regularly spaced, creating valleys 553 therebetween asshown in FIG. 5E. Internal circuitry 533 can be located in the valleys553. In an exemplary embodiment, the longitudinal ribs 550 have a widthin the range of 0.5 to 2 mm, and a height that varies from approximately6 mm in the posterior region 524 to 1 mm in the anterior region 528. Insome embodiments, the longitudinal ribs are irregularly spaced, with thespacing between ribs being larger towards the perimeter of the outershell 505 and smaller towards a central portion of the outer shell 505.In some embodiments, the longitudinal ribs are separated by a distancein the range of 4 to 9.0 mm as measured from center to center. Thetransverse ribs 551 can be located in the posterior region 524 andtraverse a width of the housing 504. The transverse ribs can be spacedregularly, as shown in FIG. 5E. In an exemplary embodiment, thetransverse ribs 551 have a width of in the range of 0.5 to 1.5 mm, and aheight of in the range of 4 to 7 mm. In some embodiments, the transverseribs 551 can intersect with the longitudinal ribs 550, creating pockets555 as shown in FIG. 5E. Internal circuitry 533 can be located in thepockets 555. In some embodiments, the transverse ribs are irregularlyspaced, with the spacing between ribs being larger towards the perimeterof the outer shell 505 and smaller towards a central portion of theouter shell 505. The column 552 can have a rectangular cross section andbe located in an anterior region 528 of the housing 504. In someembodiments, one or more columns 552 are regularly spaced and traverse awidth of the housing 504. The columns 552 can provide resistance tocompressive forces exerted on the mouthpiece 500, thereby providingprotection of the internal circuitry 533. The columns 552 can have athickness in the range of 0.5 to 2 mm. In some embodiments, the heightof the columns 552 is greater than the thickness of the internalcircuitry 533, thereby providing a clearance between the internalcircuitry 533 and the outer shell 505. In some embodiments, the heightof the columns 552 is at least 1 mm greater than the thickness of theinternal circuitry 533. In some embodiments, the platform 558 isdirectly connected to one or more longitudinal ribs and one or moretransverse ribs, thereby providing increased capacity to withstand shearand compressive loads. The thickness of the platform 558 can be in therange of 1.5 to 3.5 mm. In some embodiments, the shoring 554 includes alayer of material with a thickness greater than the thickness of theouter shell 505. The thickness of the shoring 554 can be in the range of0.5 to 2 mm. In some embodiments, the thickness of the outer shell 505is smaller in the region of the shoring 554 than in other regions toaccommodate the spacer 508. For example, the thickness of the outershell can be 1.5 mm in the anterior and posterior regions and 0.5 mm inthe region of the shoring 554. During operation, a patient places aportion of the mouthpiece 500 in his/her mouth to engage in an NINMtherapy session. The patient bites down on the mouthpiece 500 withhis/her front teeth to secure a position of the mouthpiece. Thepatient's bottom teeth contact the printed circuit board 532 and thepatient's tongue contacts the electrode array 542. In some embodiments,the patient relaxes his/her mouth to secure a position of themouthpiece. The internal circuitry delivers electrical neurostimulationsignals to the patient's tongue via the electrode array 542. In someembodiments, the spacer 508 can provide a soft and comfortable bitesurface so that stress is not concentrated at small areas where thepatient's teeth contact the mouthpiece 500 during biting. For example,the spacer 508 can be made from thermoplastic polyurethane (TPU),thermoplastic elastomer (TPE), or silicone. In some embodiments, thetransverse ribs 551 are located in the anterior region and traverse awidth of the housing 504.

FIGS. 6A-6B show a more detailed view of the outer shell 505. The outershell includes a glue well 570, internal fins 561 and 562, and a centrallongitudinal axis 590. The internal fins include at least one pair ofentrance fins 561. The entrance fins 561 can be symmetric about thelongitudinal axis 590 and can guide the cable 544 along the longitudinalaxis 590 without causing substantial bending thereof. A glue, adhesive,or epoxy can provide a rigid mechanical connection between the cable 544and the entrance fins 561. For example, the glue, adhesive, or epoxy canbe a UV cured adhesive, or cyanoacrylate. The internal fins also ininclude an even number of guiding fins 562. In some embodiments, theinternal fins include an odd number of guiding fins 562. For example,the internal fins can include three guiding fins. In some embodiments,the guiding fins 562 are not symmetric about the longitudinal axis 590,with each guiding fin 562 causing an approximately 90 degree bend in thecable 544, and each bend having a radius of curvature approximatelyequal to two diameters of the cable 544. In some embodiment, eachguiding fin 562 causes a bend in the cable 544 of greater than 90degrees, but less than 180 degrees. The guiding fins 562 are inmechanical contact with the cable 544 and provide frictional resistancethat compensates for any tensile strain applied to the cable, forexample due to longitudinal forces applied along the cable 544. In someembodiments, the guiding fins 562 provide frictional resistance of atleast 100 Newtons. In some embodiments, the guiding fins providefrictional resistance greater than the weight of the mouthpiece. In someembodiments, the guiding fins provide frictional resistance greater thanthe forces required to disconnect the mouthpiece 140 from the controller120. In some embodiments, a rubber grommet 563 provides an elasticmechanical attachment between the outer shell 505 and the cable 544 withthe outer shell 505 providing a resistance that counteracts any bendingstrain applied to the cable 544 (e.g., the patient may accidentally pullor tug on the cable while the mouthpiece 500 is secured within thepatient's mouth). In some embodiments, the spacer 508 includes anelastomeric element that provides a mechanical connection between thecable 544 and the entrance fins 561. The elastomeric element provides africtional force that provides a frictional resistance that counteractsany bending stress applied to the cable 544. In some embodiments, thecable 544 can exit the outer shell at a 90 degree angle and be attachedto the outer shell by an epoxy, the epoxy providing mechanicalresistance of up to 100 Newtons to accommodate bending strains inducedby the patient. In some embodiments, the cable 544 is attached to theouter shell by an adhesive or glue. In some embodiments, the cable 544can exit the outer shell at a 90 degree angle and be mechanicallyattached to the outer shell by a right-angled elastomeric element, theright-angled elastomeric element interlocking with the outer shell andproviding mechanical resistance of up to 100 Newtons to accommodate bothbending and tensile strains induced by the patient.

FIG. 6C shows a more detailed cross sectional view of the glue well 570.The glue well 570 is located along an outer boundary of the outer shell505 and accommodates an adhesive (e.g., a biomedical compatible epoxy orglue) that provides a mechanical connection between the printed circuitboard 532 and the outer shell 505. The glue well 570 includes a beveledlip 571, and a discontinuously connected cross-section that includes aconcave portion 572 and a vertical portion 573 that intersect to form alowest point of the glue well 570. In some embodiments, the shape of theglue well can be trapezoidal. In some embodiments, the shape of the gluewell can be wedged. In some embodiments, the shape of the glue well canbe triangular. In some embodiments, the shape of the glue well can berectangular. In some embodiments, a portion of the glue well canoverhang the printed circuit board 532, thereby protecting portions ofthe printed circuit board from the teeth of the patient. In someembodiments, the adhesive is in contact with the outer shell 505 and thetop of the printed circuit board 532. In some embodiments, the adhesiveis in contact with the outer shell 505 and the top and side portions ofthe printed circuit board 532. In some embodiments, the glue well isshaped such that the adhesive is in contact with the outer shell 505 andthe side portions of the printed circuit board 532, but only hasnegligible contact with the top portion of the printed circuit board 532(e.g., the glue well can have a width greater than a depth).

FIG. 6D shows an embodiment where the outer shell 505 includes two gluewells, 570 and 574. A first glue well 570 and a second glue well 574 arelocated along an outer boundary of the outer shell 505 and accommodatean adhesive (e.g., a biomedical compatible epoxy) that provides amechanical connection between the printed circuit board 532 and theouter shell 505. The second glue well 574 is designed to accommodate aglue or adhesive that overflows from the first glue well 570, therebypreventing glue or adhesive from overflowing onto the bottom side of theprinted circuit board. A step 578 is positioned between the first andsecond glue well to define the height of the first glue well.

FIGS. 7A-7C show a mouthpiece 700. The mouthpiece 700 includes an outershell 705 having a central longitudinal axis 790, a spacer 708, a cable744, a sleeve 764, exit fins 761, a glue well 770. The sleeve 764 isintegrated with the cable 744 and mechanically couples the cable 744with the outer shell 705. The sleeve 764 includes two tapered outerportions 765 and a gap 766 separating the two tapered outer portions.The cable 744 can be pulled towards the outer shell 705 until the gap766 is aligned with an outer boundary of the mouthpiece 700. Oncealigned with the outer shell 705, the sleeve 764 provides a mechanicalresistance of up to 100 Newtons to counteract both tensile and bendingstresses applied to the cable 744. The cable 744 may additionally beclamped between the printed circuit board 732 and the outer shell 705 asshown in FIG. 7C. The additional clamping can provide additionalmechanical resistance to tensile stresses applied to the cable 744.

FIGS. 8A-8D show a mouthpiece 800. The mouthpiece 800 includes an outershell 805, a spacer 808, a printed circuit board 832, a cable 844, asleeve 864, a glue well 870, and a clamp 809. A posterior portion of thecable 844 is connected to the printed circuit board 832 via solder,ribbon connector, or other mechanical connection. The sleeve 864 isintegrated with the cable 844 and mechanically couples the cable 844with the outer shell 805 and clamp 809. The sleeve 864 is similar to thesleeve 764, having two tapered outer portions and a gap. Instead ofbeing pulled through the outer shell 805 as shown in FIGS. 7A and 7B,the sleeve 864 is secured by a clamp 809 that connects to a bottomportion of the outer shell 805. The clamp 809 mechanically secures theprinted circuit board 832 to the outer shell 805 and in addition,secures the sleeve 864 to the outer shell 805. In some embodiments,adhesive or glue is added to the glue well 870 to secure the printedcircuit board 832 to the outer shell 805. The sleeve 864 providesmechanical resistance (up to 100 Newtons) to bending stresses andtensile stresses in the cable 844. The clamp 809 includes a rigidplastic portion 809 b and an elastomeric portion 809 a. The rigidplastic portion 809 b provides structural integrity, while theelastomeric portion 809 a provides a sealing mechanism. For example, theclamp 809 can be placed into contact with the outer shell 805 as shownin FIG. 8D. A narrow protrusion 810 extends from the rigid plasticportion 809 b of the clamp 809, the narrow protrusion 810 interlockingwith a recessed portion 806 of the outer shell 805. The elastomericportion 809 a contacts the outer shell 805, the glue well 870, and theprinted circuit board 832, forming an air tight seal. The air tight sealcan protect portions of the printed circuit board 832 from moisture. Insome embodiments, the clamp 809 is secured to the outer shell 805 byadding an adhesive or glue to the glue well 870 that contacts both theouter shell and the clamp.

FIGS. 9A-9C show a mouthpiece 900. The mouthpiece 900 includes an outershell 905, a printed circuit board 932, a cable 944, a glue well 970, aboot 945. The outer shell 905 includes a valley 971 and a glue well 970.The valley 971 guides the cable 944 within the outer shell 905, and theglue well 970 accommodates an epoxy or other adhesive to provide amechanical connection between the printed circuit board 932, the outershell 905, and the cable 944. The shape of the glue well 970 can be awedge shape to advantageously provide an interface between the adhesiveor epoxy and the printed circuit board 932, the outer shell 905, and thecable 944. A protrusion 946 extends from the outer shell 905 andinterlocks with a recessed portion 947 of the boot 945. The interlockedboot 945 is in mechanical contact along an outer diameter of the cable944 (e.g., the interlocked boot 945 can be in contact with the outerdiameter of the cable 944 for a distance in the range of 0.5 to 10 mm).In some embodiments, the interlocked boot 945 can be overmolded, orglued onto the cable 944. In some embodiments, the interlocked boot 945is mechanically coupled to the cable 944. The interlocked boot 945 canprovide mechanical resistance to tugging or pulling (e.g., up to 100Newtons) of the cable by the patient. In some embodiments, theinterlocked boot can provide resistance to both bending strains andtensile strains. In some embodiments, the boot 945 can cover the gluewell 970. In some embodiments, the boot 945 can be extended to coverportions of the printed circuit board 932 that are not covered by anelectrode array.

FIGS. 10A-10C show a mouthpiece 1000. The mouthpiece 1000 includes anouter shell 1005, a printed circuit board 1032, a cable 1044, a valley1071, a sealing ring 1081, and clips 1080. Epoxy and/or adhesives arenot present in mouthpiece 1000. The printed circuit board 1032 contactsthe sealing ring 1081 and is held in place by clips 1080. The clips 1080can have vertical sidewall and a downward sloping overhang as shown inFIG. 10B. In some embodiments, the clips are spaced along an innerboundary of the outer shell 1005. The cable 1044 is electricallyconnected to the printed circuit board 1032. Additionally, the sealingring 1081 forms an aperture at an anterior region of the outer shell1005, with the cable 1044 passing through the aperture. The valley 1071guides the cable 1044 from the printed circuit board 1132 to theaperture. The aperture is in contact with the cable 1044 and providesresistance to tugging or pulling of the cable 1044 by the patient. Insome embodiments, the aperture can provide resistance to both bendingand tensile strains on the cable 1044. In some embodiments, the sealingring 1081 is composed of a low durometer elastomer such as TPE, TPU, orsilicone. In some embodiments, the sealing ring can be replaced by aglue well or a layer of glue.

FIGS. 11A-11C show a mouthpiece 1100. The mouthpiece 1100 includes anouter shell 1105, a printed circuit board 1132, a cable 1144, and afastener 1191. The outer shell includes a glue well 1170, a valley 1171,and a port 1172 shaped to accommodate the fastener 1191. The glue well1170 can accommodate an epoxy or other adhesive that connects the outershell 1105 to the printed circuit board 1132. The cable 1144 is attachedto the printed circuit board 1132 via solder, ribbon cable, or othermechanical connector. The cable rests in the valley 1171 before exitingat port 1172. An O-ring surrounds the cable 1144 at the port 1172. Thefastener 1191 attaches to the outer shell 1105 at the position of theport 1172. The fastener applies a force to the O-ring that holds thecable in place at the port. The O-ring together with the fastener 1172protect the cable from pulling or tugging by the patient. In someembodiments, the O-ring and the fastener 1172 provide resistance to bothbending and tensile strain. In some embodiments, an epoxy or adhesivesurrounds the cable 1144 at the port 1172.

FIG. 12 shows a method 1200 of manufacturing a mouthpiece such as themouthpiece shown in FIGS. 5A-5F. Initially, a housing is provided (step1204). A spacer is attached to the housing (step 1208). In someembodiments, the spacer is molded directly onto the housing. In someembodiments, the spacer attached to the housing via an adhesive or glue.The housing is attached to the printed circuit board (step 1212). Insome embodiments, the housing is molded directly onto the printedcircuit board. The molded housing can wrap around the edge of theprinted circuit board and create a lip on the bottom side of the printedcircuit board for better engagement. In some embodiments, features canbe added to the printed circuit board (e.g., countersunk holes, bevelededge of the board, stepped edge of the board, tongue and groove edge ofthe board) such that when the molded housing is molded onto the board,the plastic hardens around the features to create better engagement. Insome embodiments, the housing is attached to the printed circuit boardvia an adhesive and/or mechanical clips. In some embodiments, thehousing is attached to the printed circuit board by a mechanical bond.In some embodiments, the housing is attached to the printed circuitboard by a chemical bond. In some embodiments, the attached housingcovers and encapsulates surface mounted electronics on the printedcircuit board, while leaving the electrode array exposed such that theelectrode array can be placed in contact with a patient's tongue forNINM therapy. A cable is provided (step 1216). The cable is connected tothe printed circuit board (step 1220). In some embodiments, the cable isconnected to the printed circuit board prior to the housing being moldedonto the printed circuit board. The cable can be partially encapsulatedby the housing after the molding process. In some embodiments, thehousing is molded onto the printed circuit board in two steps. In afirst step a first shot of plastic can be molded onto the board, wherethe mold temperatures and pressures are low enough that it is nothazardous to the electrical components on the board. The first shot canbe used to pot the components, thereby protecting them. The first shotcan be a softer material (TPE, TPU) or a rigid material with a lowermold pressure and/or temperature (Polyamide, Polyolefin). A second shotis molded over at least a portion of the first shot, where moldtemperatures and pressures are higher than the first shot. This secondshot may be of harder, more durable materials (e.g., nylon or glassfilled nylon, ABS, PC, etc.). In some embodiments, the housing is moldedonto, and completely surrounds the printed circuit board, such that onlythe electrode array is not covered by the housing. In this situation,the printed circuit board material would not come into contact with thepatient, thereby protecting the patient in the case of harmful printedcircuit board materials. In some embodiments, the electrode array isnon-planar with the printed circuit board (e.g., the electrode array canprotrude by a distance in the range of 0.1 to 1 mm from the printedcircuit board). In some embodiments, the electrode array is an array ofpins that protrude from the printed circuit board. The array of pinsremains exposed after molding the housing onto the printed circuitboard.

FIGS. 13A and 13B show a mouthpiece 1300 that has been manufactured byovermolding a housing 1304 directly onto a printed circuit board 1332.The mouthpiece 1300 includes a spacer 1308 and a cable 1344. In someembodiments, the printed circuit 1332 board includes features formechanically engaging the molded housing 1304 (e.g., a beveled edge ofthe board, a stepped edge of the board, a notched edge of the boardetc.). In some embodiments, the molded housing 1304 can wrap around theedge of the printed circuit board 1332 and create a lip on the bottomside of the printed circuit board to mechanically engage the printedcircuit board 1332. In some embodiments, the printed circuit boardincludes countersunk holes 1340. The countersunk holes are filled withplastic as the housing 1304 is molded onto the printed circuit board. Arivet forms inside the countersunk hole 1340, with the rivet being anintegral portion of the housing 1304. The tapered shape of the rivetprovides a force that holds the printed circuit board 1332 in mechanicalcontact with the housing 1304.

FIG. 14 shows a mouthpiece 1400 according to a two shot injectionmolding manufacturing method wherein a shot refers to the volume ofmaterial that is used to fill a mold cavity and compensate for materialshrinkage. The mouthpiece 1400 includes a housing 1404, a printedcircuit board 1432, a cable 1444, and a frame 1450. The frame 1450 isformed around the printed circuit board (one or both sides) 1432 duringa first shot, which provides a seal between the printed circuit boardand the external environment. The housing 1404 is formed around theprinted circuit board 1432 and frame 1450 during a second shot, therebyencapsulating the components on the printed circuit board 1432 andchemically bonding to the frame 1450. The first and second shots can berigid, elastomeric, or a combination of both.

The terminology used herein is for the purpose of describing particularembodiments and is not intended to be limiting of the inventiveconcepts. It will be understood that, although the terms first, second,third etc. are used herein to describe various elements, components,regions, layers and/or sections, these elements, components, regions,layers and/or sections should not be limited by these terms. These termsare only used to distinguish one element, component, region, layer orsection from another element, component, region, layer or section. Thus,a first element, component, region, layer or section discussed belowcould be termed a second element, component, region, layer or sectionwithout departing from the teachings of the present application.

While the present inventive concepts have been particularly shown anddescribed above with reference to exemplary embodiments thereof, it willbe understood by those of ordinary skill in the art, that variouschanges in form and detail can be made without departing from the spiritand scope of the present inventive concepts described and defined by thefollowing claims.

1.-31. (canceled)
 32. A method of manufacturing a mouthpiece, themouthpiece providing non-invasive neuromodulation to a patient, themethod comprising: providing a printed circuit board, the printedcircuit board having electronic circuitry and a plurality of electrodesfor delivering subcutaneous local electrical stimulation to thepatient's tongue; forming an elongated housing directly onto the printedcircuit board; and attaching a spacer to the top surface of theelongated housing for minimizing contact between a patient's upper teethand a top surface of the elongated housing.
 33. The method of claim 32further comprising forming a strain relief mechanism integral with theelongated housing.
 34. The method of claim 33 further comprisingproviding a cable having a first segment disposed within the housing anda second segment extending from the housing.
 35. The method of claim 34further comprising connecting one end of the first segment of the cableconnected to the printed circuit board.
 36. The method of claim 32further comprising encapsulating the electronic circuitry located on theprinted circuit board.
 37. The method of claim 32 wherein forming theelongated housing further comprises forming a frame around at least oneside of the printed circuit board, the frame providing a seal betweenthe printed circuit board and an external environment.
 38. The method ofclaim 37 further comprising forming the elongated housing around theprinted circuit board and the frame to encapsulate one or morecomponents mounted on the printed circuit board and chemically bond theelongated housing to the frame.
 39. The method of claim 32 whereinforming the elongated housing further comprises: providing a cablehaving a first segment and a second segment; connecting one end of thefirst segment of the cable to the printed circuit board; andencapsulating a portion of the cable such that the first segment of thecable is disposed within the elongated housing and the second segment ofthe cable extends from the elongated housing.
 40. The method of claim 32further comprising mechanically engaging the elongated housing with theprinted circuit board using one or more features of the printed circuitboard.
 41. The method of claim 40 wherein the one or more features ofthe printed circuit board comprises at least one of a beveled edge, astepped edge, a notched edge, and a countersunk hole.